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Dynamics of chromosome organization and chromatin states in single cells

Award Number: U01DK127420
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/19/2020
PERIOD OF PERFORMANCE END DATE: 10/31/2025

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Dynamics of chromosome organization and chromatin states in single cells - SUMMARY Cellular differentiation involves tightly coupled changes in gene expression, chromatin state, and sub-nuclear arrangements of chromosomes. Understanding and controlling differentiation requires understanding how each of these processes occurs dynamically within the same cell and how they influence one another. Existing techniques can provide genome scale analysis of interactions or spatial organization of a few chromosomal positions. However, we have lacked a generalizable framework for simultaneous reconstruction of the overall dynamics of the nucleus across all three levels. Recent work from our labs has opened up the possibility of achieving such coupled analysis. Our track first, identify later approach allows many DNA to be simultaneously tracked in living cells. RNA and DNA seqFISH allows a large number of transcripts and DNA loci to be imaged in single fixed cells and MEMOIR allows lineage information to be recovered from endpoint measurements. In this project, we propose to combine live imaging, multiplexed RNA, DNA, and immunofluorescence measurements, and MEMOIR lineage tracking to capture whole- genome dynamics of chromosomal loci and chromatin states. Using mouse embryonic stem cells (mESCs) as a model system, we will study the transition from the pluripotent state to an earlier 2- cell (2C) like state which shows drastic chromosome re-arrangement and changes in nascent gene expression patterns. In addition, we will study the chromosomal dynamics of X-inactivation based on the initial observations that sister X chromosomes are in contact with each other during early phases of the inactivation process. Both of these biological questions require tracking chromosomal dynamics and chromatin state simultaneously in single cells. The “Track First and ID later” approach allows a large number of loci to be tracked in living cells. The combined MEMOIR approach with multiplex immunofluorescence allows us to infer the kinetics of chromatin states transitions. Bringing these tools to study X inactivation and 2C state transition will demonstrate the capability of this approach for addressing a broad range of cell fate decision questions. We will also develop analysis and visualization tools to integrate genomics (SPRITE) and imaging data. The technology developed in this project can be readily implemented in human cell lines and adopted by other labs in the 4DN consortium.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Trans-NIH Research Support	000	5	9/19/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $1,136,227 )
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Trans-NIH Research Support	001	5	6/26/2024	NON-COMPETING CONTINUATION	$1,136,227
2024	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Trans-NIH Research Support	000	4	5/23/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,136,227

Issue Date FY: 2023 ( Subtotal = $1,136,227 )
2023	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Trans-NIH Research Support	001	4	8/8/2023	NON-COMPETING CONTINUATION	$1,136,227
2023	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Trans-NIH Research Support	000	3	4/4/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,136,227

Issue Date FY: 2022 ( Subtotal = $1,136,227 )
2022	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Trans-NIH Research Support	001	3	7/7/2022	NON-COMPETING CONTINUATION	$1,136,227
2022	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Trans-NIH Research Support	000	2	11/16/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,136,227

Issue Date FY: 2021 ( Subtotal = $1,136,227 )
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Trans-NIH Research Support	000	2	7/23/2021	NON-COMPETING CONTINUATION	$1,136,227
														Subtotal = $1,136,227

Issue Date FY: 2020 ( Subtotal = $1,136,227 )
2020	2020	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Trans-NIH Research Support	000	1	9/19/2020	NEW	$1,136,227
														Subtotal = $1,136,227

Grand Total All Awards = $5,681,135

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Dynamics of chromosome organization and chromatin states in single cells

Award Number: U01DK127420

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/19/2020

PERIOD OF PERFORMANCE END DATE: 10/31/2025

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